Tularemia is a Holarctic zoonosis caused by Francisella tularensis, a highly infectious, nonspore-forming, aerobic, gram-negative coccobacillus. It may infect a wide range of hosts, including invertebrates, mammals, amphibians and birds. Human infection occurs through contact with infected animals, contaminated environments or via arthropod vectors. Tularemia is endemic throughout most of Europe, northern and central Asia, and North America. Although previously thought to be absent from the southern hemisphere, autochthonous human cases were documented in Tasmania in 2011. Francisella tularensis is regarded as a potential bioterrorism agent owing to its low infectious dose and multiple routes of transmission, including inhalation, arthropod bites, direct animal contact and ingestion of contaminated food or water.1 Human-to-human transmission has not been reported. Four subspecies of F. tularensis are recognized, of which 2 are clinically relevant. Francisella tularensis subsp. tularensis (type A) is the most virulent and occurs only in North America (United States and southern Canada), with ticks serving as important vectors. Type A is further divided into A-I and A-II. Within A-I, 2 sub-lineages are distinguished: A-Ia and the more virulent A-Ib, which exhibits greater intrinsic pathogenicity compared with A-Ia, A-II or type B strains. A-I occurs predominantly in the central and eastern United States, whereas A-II is more common in the western United States. In contrast, F. tularensis subsp. holarctica (type B) predominates in Europe and Asia, typically producing a milder clinical course characterized by localized disease forms. Mortality in treated cases is generally low (<1%), but may increase depending on the infecting subspecies, clinical form, timing of treatment and host immune status.2,3 Tularemia is increasingly described as an emerging zoonosis.4–6 In this review, we use “emerging” to capture both (1) true increases in incidence driven by ecological and behavioral changes affecting reservoir dynamics, vector distribution and human exposure, and (2) increased detection resulting from improved awareness, diagnostics and surveillance systems. Where possible, we indicate whether reported trends likely represent changing transmission patterns versus improved recognition. EPIDEMIOLOGY In endemic areas, tularemia typically shows a slight male predominance and bimodal age distribution, with peaks in young children ≤9 years of age and older adults (50–60 years). Although still categorized as a rare infectious disease, the average annual tularemia incidences are increasing in different regions across the northern hemisphere.3 In the United States, surveillance data indicate a modest rise in average annual incidence in the past decade compared with earlier periods. Cases occur predominantly between May and October, mirroring seasonal patterns of tick activity, vegetation development, host availability and increased human outdoor exposure.7 In Europe, incidence has also shown a gradual increase in recent years, with the highest case numbers reported from northern and central European countries including Sweden, Norway, Finland, Switzerland and Germany.8–12 Seroprevalence studies suggest that population-level exposure to F. tularensis remains low overall, although higher rates have been observed in North America and among groups with increased occupational or environmental exposure. Importantly, most seropositive individuals report no prior history of clinically apparent tularemia.13 A genomic study from Türkiye identified multiple clades of type B linked to pediatric oropharyngeal tularemia, suggesting that strain diversity may affect clinical presentation and transmission dynamics.14 Collectively, these findings underscore the importance of region-specific surveillance, particularly in areas with high pediatric disease burden, and highlight the role of ecologic and behavioral factors in shaping tularemia epidemiology. VECTORS, TRANSMISSION AND RESERVOIRS Francisella tularensis has one of the broadest host ranges of any known zoonotic pathogen, infecting more than one hundred species, including small mammals (eg, rodents, rabbits and hares), domestic animals, birds, amphibians and a variety of arthropod vectors. Transmission to humans occurs through multiple routes, with arthropod vectors playing a leading role. In North America, ticks and deer flies; in western and central Europe, ticks are the predominant vectors; whereas in northern Europe, particularly Sweden and Finland, mosquitoes account for most cases. Direct contact with infected animals, especially rabbits, hares and rodents, can lead to infection through skin abrasions or mucous membranes.1,15 Ingestion of contaminated water or undercooked meat is a common transmission route in parts of southeastern Europe and Türkiye, where it is frequently associated with oropharyngeal tularemia.12 Inhalation of aerosolized particles from contaminated soil, hay or animal carcasses can result in pneumonic tularemia, the clinical form associated with the highest mortality, particularly when infected with F. tularensis subsp. tularensis (type A). Two principal ecological cycles maintain F. tularensis in nature. In the terrestrial cycle, wild mammals such as hares and mice serve as amplifying hosts, with subsequent spread to humans via arthropod bites. In the aquatic cycle, the pathogen persists in water contaminated with excreta or carcasses of infected animals. Furthermore mosquito larvae can become infected, with the bacterium persisting through to the adult stage, enabling further transmission. This creates a source for human infection through mosquito bites, ingestion or contact.16 These ecological reservoirs enable F. tularensis to persist in the environment and re-emerge over time. Furthermore, environmental persistence of F. tularensis in water, mud and animal carcasses for prolonged periods further facilitates seasonal outbreaks in endemic regions. The risk of tularemia outbreaks in humans is strongly linked to fluctuations in rodent populations, which are increasingly influenced by climate variability.6,15 Global warming is expected to expand the habitats of both rodent hosts and arthropod vectors, thereby intensifying opportunities for spillover at the wildlife–human interface.6,15 These dynamics highlight the potential for tularemia to expand as an emerging zoonosis and underscore the importance of sustained surveillance and preparedness in both endemic and nonendemic regions. PATHOGEN CHARACTERISTICS After entering the host, F. tularensis survives and replicates within macrophages using a type VI secretion system encoded by the Francisella pathogenicity island. It escapes the phagosome, avoids lysosomal degradation, modulates immune responses and spreads systemically.17 The pathophysiology of F. tularensis infection reveals a unique ability to evade and suppress the host immune response, contributing more to the persistence and dissemination of infection rather than an immediately fulminant course. This helps explain the often-insidious clinical onset in several forms of tularemia, such as the glandular and oropharyngeal tularemia, where local lymphadenopathy and low-grade systemic symptoms may persist for weeks. Francisella tularensis avoids destruction by escaping from the phagosome into the cytosol, where it can replicate while evading key antimicrobial mechanisms such as nicotinamide adenine dinucleotide phosphate oxidase–mediated killing and oxidative stress. This intracellular survival contributes to the strong immunopathology seen in severe pneumonic and septicemic tularemia, where impaired neutrophil responses and Nlrp3-driven inflammation play major roles in tissue injury and clinical severity.18 Because of its intracellular nature, effective therapy requires antibiotics with adequate intracellular activity.19 Recommended agents include aminoglycosides, fluoroquinolones, and tetracyclines. Fortunately, resistance has not been a concern to date. Experimental models suggest that resistance, especially to fluoroquinolones, may develop under selective pressure.20 CLINICAL MANIFESTATIONS AND COMPLICATIONS IN CHILDREN In children, tularemia most commonly presents as ulceroglandular tularemia.2,21 The clinical forms depend on the route of infection (Table, Supplemental Digital Content 1, https://links.lww.com/INF/G561). In endemic regions like Türkiye, particularly rural areas, oropharyngeal tularemia predominates due to ingestion of contaminated water. A multicenter Turkish study of 100 pediatric cases reported cervical lymphadenopathy, fever and frequent tonsillitis, with over half requiring surgical drainage due to lymph node suppuration.11,14 In contrast, central and western European cohorts more frequently report ulceroglandular and glandular tularemia, typically following tick bites or animal contact.16,22 A French series of 94 children found ulceroglandular tularemia in 46.7%, followed by glandular (17%) and oropharyngeal (18.1%) tularemia. Fever was universal, and hospitalization was required in 63%, often for antimicrobial therapy or surgical intervention. Other less common forms include oculoglandular tularemia, associated with direct ocular exposure, and pneumonic tularemia, following inhalation of aerosols, both rare in children.16,23 Furthermore, tularemia may be the cause of fever of unknown origin. The typhoidal form, a severe systemic illness without localized signs, is uncommon but associated with high mortality.24 Delayed diagnosis is frequent due to nonspecific symptoms and overlap with common childhood infections. This may lead to complications such as suppurative lymphadenitis, abscess formation, and meningitis. Surgical intervention is reported in up to 60% of pediatric cases.16,22 DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS After entry, F. tularensis spreads via the lymphatics to regional nodes and may disseminate to the spleen, liver, lungs or central nervous system. Children typically present with flu-like symptoms and regional lymphadenopathy, which often mimic common pediatric conditions such as streptococcal or staphylococcal lymphadenitis, cat-scratch disease, Epstein–Barr virus infection and atypical mycobacterial infections.2 The nonspecific presentation and rarity of tularemia frequently lead to delayed diagnosis.1,2,16,22 A thorough exposure history including tick bites, animal contact or untreated water consumption along with awareness of local endemicity is crucial for clinical suspicion. On examination the review of the skin, including scalp, and the lymphatic system is key to find an ulcer or lymphadenopathy.16,21 The laboratory diagnosis relies on serology (including immunochromatography and enzyme-linked immunosorbent assay), polymerase chain reaction (PCR) and culture. Samples of ulcers or lymph node aspirates can be used for PCR (fast and high specificity) and culture.25 As a practical diagnostic approach in suspected pediatric tularemia, in children presenting with persistent fever and regional lymphadenopathy that do not respond to empiric beta-lactam antimicrobials, tularemia should be considered, particularly when there is a history of relevant environmental exposure, animal contact or residence in endemic areas.1,2,16,22 A focused diagnostic approach is essential and should prioritize sampling from skin lesions or affected lymph nodes for PCR testing, which allows rapid and highly specific detection. Serologic assays may complement molecular methods, especially in later stages of disease or when direct sampling is not feasible. Prompt notification of the microbiology laboratory is crucial to guide testing strategies and adherence to biosafety precautions.1,25 TREATMENT The cornerstone of tularemia management is the early initiation of effective antibiotic therapy, tailored to disease severity, age and clinical form. Francisella tularensis is intrinsically resistant to beta-lactam antimicrobials. Gentamicin remains the preferred first-line treatment for severe cases due to its potent bactericidal activity. For mild to moderate disease, oral ciprofloxacin is highly effective. Doxycycline is effective; however, it is associated with higher relapse rates. Choice of therapy should be guided by clinical form, disease severity (Table, Supplemental Digital Content 1, https://links.lww.com/INF/G561).26 Standard treatment durations (10–14 days) are generally adequate; however, clinical improvement, particularly resolution of lymphadenopathy, may be delayed despite the microbiological clearance. Persistent lymph node enlargement alone should not be interpreted as treatment failure, but rather as prolonged inflammation, and may persist for several weeks following appropriate therapy. The frequency of such post-treatment symptoms appears to be low but is variably reported, reflecting limited pediatric-specific data.27 Surgical management, including incision and drainage or excision of affected lymph nodes, should be reserved for selected cases with established suppurative lymphadenitis or abscess formation that fail to respond to appropriate antimicrobial therapy. Importantly, high rates of surgical intervention reported in pediatric series often reflect delayed diagnosis or initial mismanagement rather than an inherent requirement for surgery.22,28 Early recognition and timely initiation of effective antibiotics may prevent progression to suppuration and reduce the need for invasive procedures. ONE HEALTH PERSPECTIVES, PREVENTION AND FUTURE DIRECTIONS Tularemia is an emerging zoonosis because of global environmental changes, facilitated by warmer temperature, altered seasonal patterns, thereby supporting larger and expanding vector and reservoir populations. Human exposure to the pathogen and its vectors is increased by rising participation in outdoor and recreational activities (eg, hunting, landscaping, hiking).4 Urban encroachment increases human contact with wildlife reservoirs, exposure to infected animals, contaminated water or arthropod vectors. Agricultural and land-use changes disturb rodent habitats, enabling transmission.8 Better recognition in the form of clinical awareness, availability of molecular and serologic diagnostics means cases are identified more readily, making the disease appear increasingly common. These phenomena highlight the need for a One Health approach. Coordinated efforts between human, animal and environmental health sectors are essential for early outbreak detection, integrated surveillance and more effective public health responses.4 Prevention relies on a multifaceted approach targeting environmental, vector-borne and zoonotic transmission pathways. Effective prevention requires pediatric-focused strategies, including the use of protective clothing, environmental protection agency-registered insect repellents, avoidance of untreated water, routine tick checks, hygiene reinforcement, and targeted public education. Currently, no Food and Drug Administration–approved vaccine exists for tularemia.29 Although the Live Vaccine Strain, developed over 5 decades ago, has shown to be safe and immunogenic in clinical trials, it remained unlicensed due to concerns about its stability and the risk of reversion to virulence.30 Efforts to develop new, safer vaccine candidates are ongoing. Children represent an important at-risk group for tularemia because they have more environmental exposure, a higher likelihood of animal and vector contact, and distinct patterns of behavior that facilitate transmission. However, pediatric-specific evidence guiding diagnosis and treatment remains limited. Most recent recommendations associated with antimicrobial choice, such as aminoglycosides, fluoroquinolones and doxycycline, and duration of treatment in children are extrapolated from adult studies, case series or expert opinion.26,31 Therefore, uncertainties persist regarding optimal dosing, treatment duration and relapse risk in pediatric age groups, particularly the younger age-groups, might need off-label use of some of the effective agents like ciprofloxacin, levofloxacin and gentamicin. This evidence gap may contribute to variability in clinical practice and raises concerns about the exact timing of treatment duration or delayed recognition of relapses. Given the scarcity of pediatric data, multicenter efforts on diagnostic and therapeutic studies are needed to generate age-stratified evidence and derive standardized management protocols. CONCLUSION Tularemia is an emerging zoonosis and remains a significant yet frequently underrecognized vector-borne infection, particularly affecting children in endemic regions. Its broad spectrum of clinical presentations, risk of delayed diagnosis and the necessity for targeted antimicrobial therapy highlight the importance of early identification and appropriate management. Emerging epidemiologic trends and environmental changes further emphasize the need for heightened clinical awareness, strengthened public health surveillance and ongoing education of healthcare providers. Prioritizing pediatric-specific diagnostic approaches and treatment protocols is essential to prevent complications and reduce the disease burden in this vulnerable population.
Seyrek et al. (Mon,) studied this question.
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